Lymphotoxin-β receptor signaling complex: Role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor κB

The binding of heterotrimeric lymphotoxin, LTα(1)β(2), to the LTβ receptor (LTβR), a member of the tumor necrosis factor receptor (TNFR) superfamily, induces nuclear factor κB (NF-κB) activation and cell death in HT29 adenocarcinoma cells. We now show that treatment with LTα(1)β(2) or agonistic LTβR antibodies causes rapid recruitment of TNFR-associated factor 3 (TRAF3) to the LTβR cytoplasmic domain. Further, stable overexpression of a TRAF3 mutant that lacks the RING and zinc finger domains inhibits LTβR-mediated cell death. The inhibition is specific for LTβR cell death signaling, since NF-κB activation by LTα(1)β(2) and Fas-mediated apoptosis are not inhibited in the same cells. The mutant and endogenous TRAF3s are both recruited at equimolar amounts to the LTβR, suggesting that the mutant disrupts the function of the signaling complex. These results implicate TRAF3 as a critical component of the LTβR death signaling complex and indicate that at least two independent signaling pathways are initiated by LTβR ligation.